SPT5 stabilizes RNA polymerase II, orchestrates transcription cycles, and maintains the enhancer landscape

Highlights

Acute degradation of SPT5 reveals direct, pleiotropic SPT5 functions in transcription

SPT5 stabilizes Pol II, maintains pausing, promotes elongation, and activates enhancers
SPT5 phosphorylation at S666 and CTR1 governs pausing and termination, respectively
INTAC dephosphorylates SPT5, yet harbors SPT5-independent roles in pausing

Summary

Transcription progression is governed by multitasking regulators including SPT5, an evolutionarily conserved factor implicated in virtually all transcriptional steps from enhancer activation to termination. Here we utilize a rapid degradation system and reveal crucial functions of SPT5 in maintaining cellular and chromatin RNA polymerase II (Pol II) levels. Rapid SPT5 depletion causes a pronounced reduction of paused Pol II at promoters and enhancers, distinct from negative elongation factor (NELF) degradation resulting in short-distance paused Pol II redistribution. Most genes exhibit downregulation, but not upregulation, accompanied by greatly impaired transcription activation, altered chromatin landscape at enhancers, and severe Pol II processivity defects at gene bodies. Phosphorylation of an SPT5 linker at serine 666 potentiates pause release and is antagonized by Integrator-PP2A (INTAC) targeting SPT5 and Pol II, while phosphorylation of the SPT5 C-terminal region links to 3′ end termination. Our findings position SPT5 as an essential positive regulator of global transcription.

Graphical abstract

SPT5 stabilizes RNA polymerase II, orchestrates transcription cycles, and maintains the enhancer landscape插图

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